- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine 1, 720 Rutland Ave, Baltimore, Maryland, USA
- Department of Orthopedics, Xiangya Hospital of Central South University, Xiangya Road No.87, Changsha, Hunan Province, P.R. China
† These authors contributed equally to this work.
Academic Editor: Jean Kwun
Received: October 10, 2018 | Accepted: December 09, 2018 | Published: December 14, 2018
OBM Transplantation 2018, Volume 2, Issue 4 doi:10.21926/obm.transplant.1804031
Recommended citation: Guo Y, Grzelak M, Oh BC. Cell based Therapy in Transplantation. OBM Transplantation 2018;2(4):031; doi:10.21926/obm.transplant.1804031.
© 2018 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.
Solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) have become widely utilized procedures in today’s clinical environment, and this is due to a variety of factors. First, in recent years significant progress has been made in the investigation of the mechanisms of allograft rejection . Second, the development and application of numerous immunosuppression agents such as Tacrolimus have dramatically improved graft survival rates in organ transplantation . Although the development of modern immunosuppression agents has resulted in dramatic improvement of short-term graft survival, however, the long-term survival rates remain a challenge . Furthermore, toxicities of conventional immunosuppression, including susceptibility to a wide variety of pathogens, nephrotoxicity, diabetes mellitus, anemia, and many others [4,5,6] have now become major roadblocks in today’s clinical transplantation setting.
As a result of the challenges associated with pharmacologic immunosuppression, research groups across the world have begun focusing on generating allograft tolerance as a mechanism to promote long-term graft survival. One of the most exciting movements within this research field, that of cell-based therapies, offers a novel approach to generating graft tolerance, and when utilized within a combination therapeutic strategy, these cell-based strategies may allow for targeted allograft protection without compromising the host’s overall protective immunity. Within this framework of cell-based therapies, protocols that utilize regulatory T cells (CD4 Treg, CD8 Treg), IL-10 producing Tr1 cells , regulatory macrophages (Mreg) [8,9], tolerogenic dendritic cells (tol-DCs) [10,11], and Mesenchymal stem cells (MSCs) have emerged as the most promising approaches. In this review, the results and advances of cell-based immunosuppressive approaches in animal studies and clinical trials will be discussed and compared.
2. CD4 Regulatory T Cells
Regulatory T cells (Tregs) are an important element in the development of transplant tolerance, and they are commonly utilized in cell-based immunosuppressive protocols. The rationale behind using Tregs is that they will shift the host’s inflammatory environment from a Th1 effector response to regulatory response, thereby lowering the risk of rejection and reducing the required conventional immunosuppression. There is a wide spectrum of heterogeneity among the cells grouped as “Tregs,” and each of the subsets carries out a unique tolerance-promoting function . However, the most important Treg subset is the class of conventional Treg cells that are CD4 CD25hiFoxp3 CD127low, within which Foxp3 is a transcription factor that plays a critical role in Treg development and function [13,14,15,16]. There are multiple mechanisms by which these CD4 CD25hiFoxp3 CD127low Tregs exert their inhibitory effects and limit T cell activation, including cytotoxicity, secretion of IL-10 [17,18], disruption of IL-2 signaling , disruption of antigen presenting cell (APC) signalling [20,21], and induction of T cell anergy . While many properties and characteristics of human Tregs remain to be studied, critical advances have been made in identifying specific types and subtypes of Tregs based on their markers, in expanding Tregs in ex vivo cultures, and in elucidating the pathways by which Tregs promote immunosuppression. As a result of these advances, Tregs are becoming easier to culture and study, and research centers around the world are exploring new therapeutic applications of Tregs.
2.1 Animal Models
Within the realm of transplantation there is evidence of a useful array of Treg functions, and recent animal studies show that Tregs may interact with Calcineurin inhibitors (CNI) to control memory T cells and promote long-term graft survival . It is well-established that regulatory T cells are critical for inducing and maintaining tolerance in the transplant setting, and previous animal transplantation studies have indicated that Treg-based therapy can control allograft rejection and potentially induce tolerance through a pathway involving anti-CD4 antibodies . In one such study, the recipient and donor-derived Tregs proved to be effective in inhibiting alloreactivity both in vitro and in vivo; although interestingly the effect of donor-derived Tregs could be countered by exogenous IL-12 . Furthermore, within the field of bone marrow transplantation, regulatory T cells are proving to play an important role in containing graft-versus-host disease . In particular, ex vivo expanded CD4 CD25 regulatory T cells have the ability to inhibit graft-versus-host disease while at the same time preserving graft-versus-tumor activity [27,28]. Within the fields of solid organ transplantation, in vitro alloantigen stimulated regulatory T cells have been shown to induce long-term tolerance in both skin and cardiac transplants .
Treg utilization may also benefit from recent advances in T cell research such as the genetic engineering of T cells to overexpress transgenic TCRs, which is a research model that is currently being tested in settings such as cancer immunotherapy , autoimmune diseases  and allograft rejection [32,33]. By developing chimeric antigen receptors (CARs) on Tregs, these cells could target designated allo-antigens and induce highly specific tolerance toward a small group of antigens. In one recent study  CAR technology was used to modify Tregs, and the results indicated that CAR-Tregs exhibit more potent suppressive activity both in vitro and in human skin xenografts when compared to polyclonal Tregs. Additionally, in a separate study utilizing a murine islet transplant model, mAb-directed CARs were bound to Tregs and administered to the mice that were recipients of the islet cell transplants. The administration of these Tregs led to donor specific tolerance and extended both islet cell graft survival and secondary donor skin graft survival .
2.2 Clinical Application
Human Tregs have been well-characterized over the past two decades, and the important roles they have in human transplantation outcomes are becoming evident. In 2009, a study by Trzonkowski et al  demonstrated that ex vivo expanded Tregs are effective at preventing chronic GvHD in humans. In particular, they found that Treg infusion was associated with a significant decrease in pro-inflammatory cytokines, and they also found that if Treg administration was delayed, the prevention of GVHD was less successful. Later, in 2010 Brunstein et al  managed to prevent allogeneic acute GvHD in bone marrow transplant recipients by infusing ex vivo expanded Tregs along with a standard immunosuppressive therapy into patients. They also found that cryopreservation may negatively impact the overall functioning of Tregs. In 2011, Di Ianni et al  proved that the infusion of freshly isolated donor Tregs into bone marrow transplant recipients can make immune reconstitution with CD4 and CD8 T cell administration a feasible and safe option in the clinical setting. Finally, a study by Marek-Trzonkowska et al  showed that Treg infusion is an effective therapeutic option to prolong the length of remission of type 1 diabetes in children.
More recently, a phase 1 Treg Adoptive Cellular Transfer (TRACT) trial tested the use of Tregs in kidney transplantation through the use of polyclonal expanded Tregs from recipients’ cryopreserved leukopheresis products (NCT02145325) . A total of nine patients were enrolled in the TRACT study, and all of them received Tacrolimus and mycophenolate immediately after transplantation, followed by conversion to Sirolimus monotherapy prior to administration of Tregs. Compared to pre-transplant Treg levels, in all patients a 5-20 fold increase in Tregs was achieved at one year follow up, indicating that the Treg infusions resulted in a stably elevated Treg presence within the recipients. Additionally, the study demonstrated the long-term safety of Treg therapy in humans. The pilot TASKp trial (NCT02088931) also explored the potential of ex vivo expanded polyclonal Tregs in kidney transplantation. The TASKp trial therapy included an infusion of 320×106 Tregs into each patient, and the resulting 100-fold expansion (or greater) of infused Tregs over the course of one week resulted in the infused Treg population comprising 7.5% of the patients’ total peripheral Tregs. Furthermore, the results of a 1-year follow-up indicated decreased graft inflammation and increased uCRM scores compared to pre-Treg infusion levels. Finally, another pilot study recently applied regulatory T cell-based therapy in the setting of living donor liver transplantation. Ex vivo-produced Tregs were infused into recipients, and 7 out of 10 patients were able to completely withdraw from immunosuppression .
Through all of these clinical trials, Treg infusion has been shown to be a safe and effective method of modulating the immune system while simultaneously minimizing the use of immunosuppressive drugs. Furthermore, these studies show that the efficacy of Treg therapy is dependent on proper dosage, time of administration, and quality of the Tregs themselves. Future utilization of Treg infusion therapy will rely on the development of novel Treg expansion protocols as well as further discoveries into the mechanisms by which Tregs suppress immune functions.
3. CD8 Regulatory T Cells
While it has become well-established that CD4 regulatory T cells are critical for immune regulation, researchers have just recently discovered that some sub-populations of CD8 T cells may also act as potent regulators of immune tolerance through the promotion of suppressive activity. In humans, CD8 CD28- Tregs have been found in the settings of chronic allograft rejection [40,41,42] and autoimmune disease , and along with other CD8 subtypes including CD8 CD103  and CD8 CD122  cells, they have been shown to inhibit T cell activation and proliferation. Due to their recent discovery, the underlying inhibitory mechanisms of these CD8 Tregs have not yet been fully illustrated. However, perforin-mediated cytotoxicity, cell contact-dependent inhibition, the production of inhibitory cytokines, and the upregulation of inhibitory markers on APCs have all been linked to their suppressive activity [46,47]. Moreover, there is evidence that CD8 Foxp3 Tregs may indirectly inhibit proliferation of effector CD4 and CD8 T cells and the production of pro-inflammatory cytokines by stimulating an increase in CTLA-4 expression on dendritic cells .
3.1 Animal Models
Numerous pre-clinical research models have demonstrated the potential benefits of CD8 CD28- Tregs in the transplant setting. In ex vivo models, the CD8 CD28- Tregs have been shown to anergize xenoreactive CD4 T cells . These CD8 CD28- Tregs have also been demonstrated to have a beneficial effect on the long-term survival of rat liver transplants . Additionally, adoptive transfer of CD8 CD122 Tregs has been shown to extend graft survival in murine allogeneic islet transplantation models . Finally, the infusion of human CD8 regulatory T cells in a murine model proved to be effective in inhibiting GvHD while persevering the protective immunity of the mice .
In summary, while CD8 Tregs have only recently been discovered and there have not been any clinical trials involving their administration into human patients, they are considered a novel and promising cell population with many potential future applications in the prevention allograft rejection.
4. Tolerogenic Dendritic Cells
Dendritic cells (DCs) have become well-known as the most potent of the antigen presenting cells. As critical orchestrators of the immune response, DCs have multiple roles in the upregulation and downregulation of the immune response as well as the induction of tolerance . DCs comprise a very heterogeneous group of cells, and they can be sorted into conventional and plasmacytoid DCs based on their phenotypes and functions. Additionally, DCs can be sub-divided into immature and mature DCs based on their development stages. Of particular interest is a subpopulation of DCs known as regulatory or tolerogenic DCs (tol-DCs). These cells arise from immature DCs and function as suppressors of the immune response . Tol-DCs play a vital role in maintaining both central and peripheral tolerance, and they promote tolerance through T cell inhibition and apoptotic depletion, induction of T cell anergy, activation of Tregs, and the production of immunosuppressive cytokines such as IL-10, TGF-β and IDO [55,56]. Regarding central tolerance within the thymus, these tol-DCs enforce negative selection of self-reactive and antigen-specific reactive thymocytes. Furthermore, they also promote central tolerance by inducing regulatory T cell generation [57,58,59].
4.1 Animal Models
Many experiments have been conducted using tolerogenic DCs as a treatment both prior to and after the establishment of autoimmune disease symptoms, and the results suggest that tolerogenic DCs have a strong inhibitory effect on the development of autoimmune diseases . In rodent heart and islet cell transplant studies it has been shown that tol-DCs are capable of decreasing effector T cell frequency and inducing splenic T cell unresponsiveness to allo-antigens [61,62]. Furthermore, adoptive transfer of tol-DCs into transplant recipients has been shown to promote the development of donor-specific tolerance . In mice, a series of studies showed that when pre-transplantation adoptive transfer of tol-DCs was utilized in addition to conventional immunosuppression, the median survival of the cardiac grafts exceeded 100 days [63,64,65,66].
In non-human primate transplant models, the Thomson group showed that infusion of tol-DCs along with CTLA4-Ig administration reduced allogenic T cell responses and led to an increase in immune-modulating IL-10 producing T cells . In another non-human primate transplant study, it was shown that tol-DC administration one week prior to transplantation increased graft survival by over 70 days . Most recently, tol-DCs have also been shown to modulate the immune response by decreasing IL-17 production and promoting renal allograft survival in primate models .
4.2 Clinical Application
Tol-DCs are already being utilized in clinical trials to test for therapeutic benefits in inflammatory and autoimmune diseases such as Type 1 Diabetes , Rheumatoid Arthritis [71,72] and Crohn’s Disease . Within the transplant setting, tol-DCs, and indeed, APCs in general are beginning to enter the clinical realm. Most recently, researchers have been studying the immunosuppressive benefits of another APC, which is a donor splenic macrophage referred to as a “transplant acceptance inducing cell” (TAIC) [74,75]. In Hutchinson JA’s study on TAICs and their immunosuppressive effects after renal transplantation, his team found that 10 of 12 patients were able to gradually withdraw from the conventional immunosuppression after 8 weeks due to the addition of TAICs to the treatment protocol . Another study investigating the efficacy of regulatory macrophages (Mregs) in the renal transplant setting involved the administration of Mregs one week prior to transplantation. The patients then received multi-drug immunosuppression for 6 months before being tapered down to low-dose Tacrolimus monotherapy. Flow cytometry-based in vitro suppression assays indicated profound suppression of both CD4 and CD8 T cells in the early post-op period, and both patients in the study had stable graft function at 3 year follow-up visits . As evidenced by these numerous successful clinical and pre-clinical trials, tol-DCs and other regulatory APCs have proven to be safe for use in humans and are demonstrating promise as potent additions to post-transplantation immunosuppression protocols. Given the promising results of these initial studies, then, several new phase I/II clinical trials are now underway to further investigate the use of tol-DCs and other APCs as additions to the immunosuppressive protocol in a variety of transplant settings. (NCT02088931, NCT02091232, NCT02129881, NCT02188719, NCT02244801)
5. Mesenchymal Stem Cells
Mesenchymal stem cells (MSCs) have long been considered an exciting cell population with the potential to enhance immunosuppressive protocols while minimizing side effects. In the field of transplantation, MSCs can be exogenously cultured and infused in order to influence immune microenvironments within the host in a paracrine fashion , and the dual roles of MSCs in regeneration and immune regulation make them uniquely attractive compared to previously mentioned cell lines such as T cells and DCs. What is more, allogeneic MSCs do not trigger classic rejection episodes by the host’s immune system, and their immunomodulatory effects have shown promise in reducing cell-mediated cytotoxic effects on transplanted organs .
Mesenchymal stem cells possess a wide variety of immunoregulatory functions and have been shown to suppress the proliferation and activity of immune cells both in vivo and in vitro [1,78,79]. MSCs can suppress Th1 and Th17 cell proliferation via a contact-dependent method, and they can induce the expansion of immunomodulatory Tr1 IL-10 T cells and Th3 TGF-β T cells. One study showed that MSCs can influence the development and maturation of APCs and decrease the ability of these APCs to activate a T cell response . In addition to inhibiting lymphocyte activation and cytokine production, there are also multiple studies indicating that MSCs can stimulate the maturation of regulatory T cells and regulatory B cells .
Although therapies based on MSC administration are generating exciting results, it is important to note that there are controversies surrounding the classification and characterization of “MSCs.” Cells classified as MSCs can originate from bone marrow, skin, pancreatic tissue, the lungs, the kidneys, and many other sources. Furthermore, the term “MSC” represents such a diverse class of cells that, unlike many other stem cell types, there’s no defining epitope unique to all MSCs . As such, isolating MSCs requires an extensive enrichment process involving multiple markers, and the final enriched product may be a heterogeneous mixture of MSC subpopulations [83,84].
5.1 Animal Models
The preclinical pilot study on the immunosuppressive potential of MSCs was conducted on a baboon model by Bartholomew et al . The infusion of allogeneic MSCs led to extended skin graft survival, and the MSCs did not elicit a proliferative response from the host immune system. Since this initial trial, numerous studies have been conducted to explore the mechanisms by which MSCs influence and enhance graft survival in various transplantation models [86,87,88].
5.2 Clinical Application
The first clinical trial regarding the infusion of MSCs in a transplantation setting was reported in 2011, in which two renal transplant patients received autologous MSCs from living-related donors . Through the generation of an increase in the CD4 Treg population and a simultaneous decrease in the CD8 memory T cell population, cell-based therapies that utilized the MSCs were proven to be safe and effective in the clinical transplant setting. Currently, five completed clinical trials [90,91,92,93,94] have investigated the effects of MSC infusion in transplant patients, and all have shown MSCs to be effective immunomodulators. Furthermore, there are eight ongoing clinical trials involving MSCs in transplantation, and these trials will provide further information regarding the efficacy of MSCs in the clinical setting. (NCT02490020, NCT01690247, NCT02563366, NCT02409940, NCT01429038, NCT02561767, NCT02492308, NCT02957552)
Although MSCs are relatively new within the field of cell-based transplant treatment and their therapeutic benefits have not yet been fully elucidated, the research that has been done has shown MSCs to be a safe and promising therapeutic option of the future.
Cell based therapies within the field of transplantation are relatively new and must be rigorously standardized, optimized, and generalized before becoming a crucial addition to immunosuppressive protocols. However, with minimal side effects and clear benefits in an era of personalized medicine, cell-based therapies are ideally suited to become a new class of immunomodulatory treatments and to revolutionize our approach to developing transplant immunosuppression regimens.
Y.G., M.G., and B.O. prepared the manuscript.
The authors have declared that no competing interests exist.
- Kaundal U, Bagai U, Rakha A. Immunomodulatory plasticity of mesenchymal stem cells: a potential key to successful solid organ transplantation. J Transl Med. 2018; 16: 31. [CrossRef]
- Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004; 351: 2715-2729. [CrossRef]
- Bamoulid J, Staeck O, Halleck F, Khadzhynov D, Brakemeier S, Dürr M, et al., The need for minimization strategies: current problems of immunosuppression. Transpl Int. 2015; 28: 891-900. [CrossRef]
- Chapman JR. Chronic calcineurin inhibitor nephrotoxicity-lest we forget. Am J Transplant. 2011; 11: 693-697. [CrossRef]
- Ghisdal L, Bouchta NB, Broeders N, Crenier L, Hoang AD, Abramowicz D, et al. Conversion from tacrolimus to cyclosporine A for new-onset diabetes after transplantation: a single-centre experience in renal transplanted patients and review of the literature. Transpl Int. 2008; 2: 146-151.
- Almeida CC, Silveira MR, de Araújo VE, de Lemos LLP, de Oliveira Costa J, Reis CAL, et al. Safety of immunosuppressive drugs used as maintenance therapy in kidney transplantation: a systematic review and meta-analysis. Pharmaceuticals (Basel). 2013; 6: 1170-1194. [CrossRef]
- Gregori S, Bacchetta R, Passerini L, Levings ML, Roncarolo MG. Isolation, expansion, and characterization of human natural and adaptive regulatory T cells. Methods Mol Biol. 2007; 380: 83-105. [CrossRef]
- Riquelme P, Geissler EK, Hutchinson JA. Alternative approaches to myeloid suppressor cell therapy in transplantation: comparing regulatory macrophages to tolerogenic DCs and MDSCs. Transplant Res. 2012; 1: 17. [CrossRef]
- Hutchinson JA, Riquelme P, Sawitzki B, Tomiuk S, Miqueu P, Zuhayra M, et al. Cutting Edge: Immunological consequences and trafficking of human regulatory macrophages administered to renal transplant recipients. J Immunol. 2011; 187: 2072-2078. [CrossRef]
- Moreau A, Varey E, Bouchet-Delbos L, Cuturi MC. Cell therapy using tolerogenic dendritic cells in transplantation. Transplant Res. 2012; 1: 13. [CrossRef]
- Stoop JN, Robinson JH, Hilkens CM. Developing tolerogenic dendritic cell therapy for rheumatoid arthritis: what can we learn from mouse models? Ann Rheum Dis. 2011; 70: 1526-1533. [CrossRef]
- Povoleri GA, Scottà C, Nova-Lamperti EA, John S, Lombardi G, Afzali B. Thymic versus induced regulatory T cells - who regulates the regulators? Front Immunol. 2013; 4: 169. [CrossRef]
- Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003; 4: 330-336. [CrossRef]
- Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003; 299: 1057-1061. [CrossRef]
- Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med. 2001; 193: 1303-1310. [CrossRef]
- Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001; 193: 1285-1294. [CrossRef]
- Hara M, Kingsley CI, Niimi M, Read S, Turvey SE, Bushell AR, et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol. 2001; 166: 3789-3796. [CrossRef]
- Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity. 2004; 21: 589-601. [CrossRef]
- Carvalho-Gaspar M, Jones ND, Luo S, Martin L, Brook MO, Wood KJ. Location and time-dependent control of rejection by regulatory T cells culminates in a failure to generate memory T cells. J Immunol. 2008; 180: 6640-6648. [CrossRef]
- Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, et al., Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol. 2006; 7: 83-92. [CrossRef]
- Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med. 2006; 203: 505-511. [CrossRef]
- Kalekar LA, Mueller DL. Relationship between CD4 Regulatory T Cells and Anergy In Vivo. J Immunol. 2017; 198: 2527-2533. [CrossRef]
- Siepert A, Ahrlich S, Vogt K, Appelt C, Stanko K, Kühl A, et al., Permanent CNI treatment for prevention of renal allograft rejection in sensitized hosts can be replaced by regulatory T cells. Am J Transplant. 2012; 12: 2384-2394. [CrossRef]
- Pearson TC, Darby CR, Bushell AR, West LJ, Morris PJ, Wood KJ. The assessment of transplantation tolerance induced by anti-CD4 monoclonal antibody in the murine model. Transplantation. 1993; 55: 361-367. [CrossRef]
- Velasquez-Lopera MM, Eaton VL, Lerret NM, Correa LA, DeCresce RP, García LF, et al., Induction of transplantation tolerance by allogeneic donor-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells. Transpl Immunol. 2008; 19: 127-135. [CrossRef]
- Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med. 2002; 196: 389-399. [CrossRef]
- Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood. 2002; 99: 3493-3499. [CrossRef]
- Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003; 9: 1144-1150. [CrossRef]
- Joffre O, Santolaria T, Calise D, Saati TA, Hudrisier D, Romagnoli P, et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med. 2008; 14: 88-92. [CrossRef]
- Jain MD, Davila ML. Concise Review: Emerging Principles from the Clinical Application of Chimeric Antigen Receptor T Cell Therapies for B Cell Malignancies. Stem Cells. 2018; 36: 36-44. [CrossRef]
- Blat D, Zigmond E, Alteber Z, Waks T, Eshhar Z. Suppression of murine colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells. Mol Ther. 2014; 22: 1018-1028. [CrossRef]
- Boardman DA, Philippeos C, Fruhwirth GO, Ibrahim MAA, Hannen RF, Cooper D, et al., Expression of a chimeric antigen receptor specific for donor HLA class I enhances the potency of human regulatory T cells in preventing human skin transplant rejection. Am J Transplant. 2017; 17: 931-943. [CrossRef]
- Pierini A, Iliopoulou BP, Peiris H, Pérez-Cruz M, Baker J, Hsu K, et al., T cells expressing chimeric antigen receptor promote immune tolerance. JCI Insight. 2017; 2.
- Trzonkowski P, Bieniaszewska M, Juścińska J, Dobyszuk A, Krzystyniak A, Marek N, et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol. 2009; 133: 22-26. [CrossRef]
- Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011; 117: 1061-1070. [CrossRef]
- Di Ianni M, Falzetti F, Carotti A, Terenzi A, Del Papa B, Perruccio K, et al. Immunoselection and clinical use of T regulatory cells in HLA-haploidentical stem cell transplantation. Best Pract Res Clin Haematol. 2011; 24: 459-466. [CrossRef]
- Marek-Trzonkowska N, Myśliwiec M, Dobyszuk A, Grabowska M, Techmańska I, Juścińska J, et al. Administration of CD4+CD25highCD127- regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care. 2012; 35: 1817-1820. [CrossRef]
- Mathew JM, H.-Voss J, LeFever A, Konieczna I, Stratton C, He J, et al. A Phase I Clinical Trial with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants. Sci Rep. 2018; 8: 7428. [CrossRef]
- Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, et al. A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology. 2016; 64: 632-643. [CrossRef]
- Assadiasl S, Ahmadpoor P, Nafar M, Pezeshki ML, Pourrezagholi F, Parvin M, et al. Regulatory T cell subtypes and TGF-beta1 gene expression in chronic allograft dysfunction. Iran J Immunol. 2014; 11: 139-152.
- Dijke IE, Caliskan K, Klepper M, de Kuiper R, Balk AH, Maat AP. Donor-specific immune regulation by CD8 lymphocytes expanded from rejecting human cardiac allografts. Am J Transplant. 2009; 9: 397-403. [CrossRef]
- Sindhi R, Manavalan JS, Magill A, Suciu-Foca N, Zeevi A. Reduced immunosuppression in pediatric liver-intestine transplant recipients with CD8+CD28- T-suppressor cells. Hum Immunol. 2005; 66: 252-257. [CrossRef]
- Negrini S, Fenoglio D, Parodi A, Kalli F, Battaglia F, Nasi G, et al. Phenotypic Alterations Involved in CD8+ Treg Impairment in Systemic Sclerosis. Front Immunol. 2017; 8: 18. [CrossRef]
- Ho J, Kurtz CC, Naganuma M, Ernst PB, Cominelli F, Rivera-Nieves J. A CD8+/CD103high T cell subset regulates TNF-mediated chronic murine ileitis. J Immunol. 2008; 180: 2573-2580. [CrossRef]
- Su J, Xie Q, Xu Y, Li XC, Dai Z. Role of CD8(+) regulatory T cells in organ transplantation. Burns Trauma. 2014; 2: 18-23. [CrossRef]
- Hasegawa H, Kawahata K, Mizoguchi F, Okiyama N, Miyasaka N, Kohsaka H. Direct suppression of autoaggressive CD8+ T cells with CD80/86 blockade in CD8+ T cell-mediated polymyositis models of mice. Clin Exp Rheumatol. 2017; 35: 593-597.
- Yu Y, Ma X, Gong R, Zhu J, Wei L, Yao J. Recent advances in CD8(+) regulatory T cell research. Oncol Lett. 2018; 15: 8187-8194. [CrossRef]
- Lerret NM, Houlihan JL, Kheradmand T, Pothoven KL, Zhang ZJ, Luo X. Donor-specific CD8+ Foxp3+ T cells protect skin allografts and facilitate induction of conventional CD4+ Foxp3+ regulatory T cells. Am J Transplant. 2012; 12: 2335-2347. [CrossRef]
- Colovai AI, Liu Z, Ciubotariu R, Lederman S, Cortesini R, Suciu-Foca N. Induction of xenoreactive CD4+ T-cell anergy by suppressor CD8+CD28- T cells. Transplantation. 2000; 69: 1304-1310. [CrossRef]
- Liu Y, Chen N, Chen G, You P. The protective effect of CD8+CD28- T suppressor cells on the acute rejection responses in rat liver transplantation. Transplant Proc. 2007; 39: 3396-3403. [CrossRef]
- Dai Z, Zhang S, Xie Q, Wu S, Su J, Li S, et al. Natural CD8+CD122+ T cells are more potent in suppression of allograft rejection than CD4+CD25+ regulatory T cells. Am J Transplant. 2014; 14: 39-48. [CrossRef]
- Zheng J, Liu Y, Liu Y, Liu M, Xiang Z, Lam KT, et al. Human CD8+ regulatory T cells inhibit GVHD and preserve general immunity in humanized mice. Sci Transl Med. 2013; 5: 168ra9. [CrossRef]
- Morelli AE, Thomson AW. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol. 2007; 7: 610-621. [CrossRef]
- Fu F, Li Y, Qian S, Lu L, Chambers F, Starzl TE, et al. Costimulatory molecule-deficient dendritic cell progenitors (MHC class II+, CD80dim, CD86-) prolong cardiac allograft survival in nonimmunosuppressed recipients. Transplantation. 1996; 62: 659-665. [CrossRef]
- Ezzelarab M, Thomson AW. Tolerogenic dendritic cells and their role in transplantation. Semin Immunol. 2011; 23: 252-263. [CrossRef]
- Mosser DM, Zhang X. Interleukin-10: new perspectives on an old cytokine. Immunol Rev. 2008; 226: 205-218. [CrossRef]
- Hanabuchi S, Ito T, Park WR, Watanabe N, Shaw JL, Roman E, et al. Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J Immunol. 2010; 184: 2999-3007. [CrossRef]
- Martin-Gayo E, Sierra-Filardi E, Corbí AL, Toribio ML. Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development. Blood. 2010; 115: 5366-5375. [CrossRef]
- Besin G, Gaudreau S, Ménard M, Guindi C, Dupuis G, Amrani A. Thymic stromal lymphopoietin and thymic stromal lymphopoietin-conditioned dendritic cells induce regulatory T-cell differentiation and protection of NOD mice against diabetes. Diabetes. 2008; 57: 2107-2017. [CrossRef]
- Hilkens CM, Isaacs JD, Thomson AW. Development of dendritic cell-based immunotherapy for autoimmunity. Int Rev Immunol. 2010; 29: 156-183. [CrossRef]
- Peche H, Trinité B, Martinet B, Cuturi MC. Prolongation of heart allograft survival by immature dendritic cells generated from recipient type bone marrow progenitors. Am J Transplant. 2005; 5: 255-267. [CrossRef]
- Baas MC, Kuhn C, Valette F, Mangez C, Duarte MS, Hill M, et al., Combining autologous dendritic cell therapy with CD3 antibodies promotes regulatory T cells and permanent islet allograft acceptance. J Immunol. 2014; 193: 4696-4703. [CrossRef]
- Lutz MB, Suri RM, Niimi M, Ogilvie AL, Kukutsch NA, Rößner S, et al. Immature dendritic cells generated with low doses of GM-CSF in the absence of IL-4 are maturation resistant and prolong allograft survival in vivo. Eur J Immunol. 2000; 30: 1813-1822. [CrossRef]
- Lu L, Li W, Fu F, Chambers FG, Qian S, Fung JJ, et al. Blockade of the CD40-CD40 ligand pathway potentiates the capacity of donor-derived dendritic cell progenitors to induce long-term cardiac allograft survival. Transplantation. 1997; 64: 1808-1815. [CrossRef]
- Bonham CA, Peng L, Liang X, Chen Z, Wang L, Ma L. Marked prolongation of cardiac allograft survival by dendritic cells genetically engineered with NF-kappa B oligodeoxyribonucleotide decoys and adenoviral vectors encoding CTLA4-Ig. J Immunol. 2002; 169: 3382-3391. [CrossRef]
- Wang Q, Zhang M, Ding G, Liu Y, Sun Y, Wang J, et al. Anti-ICAM-1 antibody and CTLA-4Ig synergistically enhance immature dendritic cells to induce donor-specific immune tolerance in vivo. Immunol Lett. 2003; 90: 33-42. [CrossRef]
- Zahorchak AF, Kean LS, Tokita D, Turnquist HR, Abe M, Finke J, et al. Infusion of stably immature monocyte-derived dendritic cells plus CTLA4Ig modulates alloimmune reactivity in rhesus macaques. Transplantation. 2007; 84: 196-206. [CrossRef]
- Ezzelarab MB, Zahorchak AF, Lu L, Morelli AE, Chalasani G, Demetris AJ, et al., Regulatory dendritic cell infusion prolongs kidney allograft survival in nonhuman primates. Am J Transplant. 2013; 13: 1989-2005. [CrossRef]
- Ezzelarab MB, Raich-Regue D, Lu L, Zahorchak AF, Perez-Gutierrez A, Humar A, et al., Renal Allograft Survival in Nonhuman Primates Infused With Donor Antigen-Pulsed Autologous Regulatory Dendritic Cells. Am J Transplant. 2017; 17: 1476-1489. [CrossRef]
- Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care. 2011; 34: 2026-2032. [CrossRef]
- Benham H, Nel HJ, Law SC, Mehdi AM, Street S, Ramnoruth N, et al., Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci Transl Med. 2015; 7: 290ra87. [CrossRef]
- Bell GM, Anderson AE, Diboll J, Reece R, Eltherington O, Harry RA, et al. Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann Rheum Dis. 2017; 76: 227-234. [CrossRef]
- Jauregui-Amezaga A, Cabezón R, Ramírez-Morros A, España C, Rimola J, Bru C, et al. Intraperitoneal Administration of Autologous Tolerogenic Dendritic Cells for Refractory Crohn's Disease: A Phase I Study. J Crohns Colitis. 2015; 9: 1071-1078. [CrossRef]
- Hutchinson JA, Riquelme P, Brem-Exner BG, Schulze M, Matthäi M, Renders L, et al. Transplant acceptance-inducing cells as an immune-conditioning therapy in renal transplantation. Transpl Int. 2008; 21: 728-741. [CrossRef]
- Hutchinson JA, Brem-Exner BG, Riquelme P, Roelen D, Schulze M, Ivens K, et al., A cell-based approach to the minimization of immunosuppression in renal transplantation. Transpl Int. 2008; 21: 742-754. [CrossRef]
- Shi Y, Hu G, Su J, Li W, Chen Q, Shou P, et al. Mesenchymal stem cells: a new strategy for immunosuppression and tissue repair. Cell Res. 2010; 20: 510-518. [CrossRef]
- Loewendorf A, Csete M. Concise review: immunologic lessons from solid organ transplantation for stem cell-based therapies. Stem Cells Transl Med. 2013; 2: 136-142. [CrossRef]
- Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005; 105: 1815-1822. [CrossRef]
- Rasmusson I, Ringdén O, Sundberg B, Le Blanc K. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res. 2005; 305: 33-41. [CrossRef]
- Deng W, Han Q, Liao L, You S, Deng H, Zhao RCH. Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from BXSB mice. DNA Cell Biol. 2005; 24: 458-463. [CrossRef]
- Ma OK, Chan KH. Immunomodulation by mesenchymal stem cells: Interplay between mesenchymal stem cells and regulatory lymphocytes. World J Stem Cells. 2016; 8: 268-278. [CrossRef]
- Fitzsimmons REB, Mazurek MS, Soos A, Simmons CA. Mesenchymal Stromal/Stem Cells in Regenerative Medicine and Tissue Engineering. Stem Cells Int. 2018; 2018: 8031718. [CrossRef]
- Sacchetti B, Funari A, Remoli C, Giannicola G, Kogler G, Liedtke S, et al. No Identical “Mesenchymal Stem Cells” at Different Times and Sites: Human Committed Progenitors of Distinct Origin and Differentiation Potential Are Incorporated as Adventitial Cells in Microvessels. Stem Cell Reports. 2016; 6: 897-913. [CrossRef]
- Sipp D, Robey PG, Turner L. Clear up this stem-cell mess. Nature. 2018; 561: 455-457. [CrossRef]
- Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K, Patil S, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002; 30: 42-48. [CrossRef]
- Zhou HP, Yi DH, Yu SQ, Sun GC, Cui Q, Zhu HL, et al. Administration of donor-derived mesenchymal stem cells can prolong the survival of rat cardiac allograft. Transplant Proc. 2006; 38: 3046-3051. [CrossRef]
- Popp FC, Eggenhofer E, Renner P, Slowik P, Lang SA, Kaspar H, et al. Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate. Transpl Immunol. 2008; 20: 55-60. [CrossRef]
- Inoue S, Popp FC, Koehl GE, Piso P, Schlitt HJ, Geissler EK, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation. 2006; 81: 1589-1595. [CrossRef]
- Perico N, Casiraghi F, Introna M, Gotti E, Todeschini M, Cavinato RA, et al. Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol. 2011; 6: 412-422. [CrossRef]
- Reinders ME, de Fijter JW, Roelofs H, Bajema IM, de Vries DK, Schaapherder AF, et al. Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med. 2013; 2: 107-111. [CrossRef]
- Peng Y, Ke M, Xu L, Liu L, Chen X, Xia W, et al. Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation. 2013; 95: 161-168. [CrossRef]
- Tan J, Wu W, Xu X, Liao L, Zheng F, Messinger S, et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA. 2012; 307: 1169-1177. [CrossRef]
- Perico N, Casiraghi F, Gotti E, Introna M, Todeschini M, Cavinato RA. Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation. Transpl Int. 2013; 26: 867-878. [CrossRef]
- Vanikar AV, Trivedi HL, Kumar A, Gopal SC, Patel HV, Gumber MR, et al. Co-infusion of donor adipose tissue-derived mesenchymal and hematopoietic stem cells helps safe minimization of immunosuppression in renal transplantation - single center experience. Ren Fail. 2014; 36: 1376-1384. [CrossRef]